HER2 Testing and Treatment / NSCLC 07/16/2026

Multidisciplinary Team Discusses Diagnosing and Treating HER2–Positive NSCLC

A professional woman with dark hair and a friendly smile, wearing business attire, in a corporate environment. Charu Aggarwal, MD, MPH A smiling male medical professional in a suit and glasses at a conference, representing oncology updates and medical research. Samuel Caughron, MD Professional male in a suit, healthcare expert, oncology specialist, headshot for OncUpdates, medical professional portrait, cancer research and treatment authority. Paolo Tarantino, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Oncologist smiling in white coat, highlighting cancer research and treatment expertise, with a bow tie, in a bright medical setting. Rohit Gosain, MD

Key Points

  • Both next-generation sequencing (NGS) and immunohistochemistry (IHC) testing are needed to screen for HER2 positivity in patients with non-small cell lung cancer (NSCLC).
  • Approved targeted therapies for HER2–positive NSCLC include trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), and zongertinib or sevabertinib, two tyrosine kinase inhibitors.
  • Trials showing that T-DXd is effective in lower-HER2-expression subgroups have rapidly shifted the understanding and interpretation of HER2 positivity in pathology reports.

Diagnosing and Treating HER2–Positive NSCLC

For the Oncology Brothers podcast Clinical Insights series, co-hosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, hosted a panel discussion on testing and treatment options for human epidermal growth factor receptor 2 (HER2)–positive lung cancer. The panel featured Charu Aggarwal, MD, MPH, a thoracic medical oncologist at Penn Medicine; Samuel Caughron, MD, a pathologist at Mawd Pathology Group; and Paolo Tarantino, MD, a breast medical oncologist at Dana-Farber Cancer Institute.

HER2–Positive Lung Cancer: Incidence and Workup 

Targeted therapies against HER2 were initially developed for breast cancer. Over time, HER2 mutation, gene amplification, and protein overexpression have been discovered in several other cancers, including lung cancer. HER2 mutations occur in approximately 2% to 4% of lung adenocarcinomas, more commonly in females and never-smokers. HER2 protein overexpression occurs in approximately 2% to 38% of all lung cancers, depending on criteria. HER2 overexpression is also predominantly seen in adenocarcinomas and is usually associated with a papillary-predominant histology, said Dr. Aggarwal.

Given the multitude of targetable alterations in NSCLC, every patient should undergo upfront DNA and RNA NGS to guide frontline treatment. Liquid biopsy NGS may be effective for making rapid initial treatment decisions and for monitoring for resistance mutations upon progression, although tissue biopsy NGS remains the gold standard. In addition, tissue samples are required for IHC testing to screen for PD-L1, HER2, and c-Met overexpression. In general, HER2 genetic alterations and HER2 protein overexpression are mutually exclusive, and workup procedures should screen for both, said Dr. Caughron.

HER2–Targeted Therapies in NSCLC

Zongertinib, sevabertinib, and T-DXd are targeted therapies approved for HER2–mutated advanced NSCLC. While zongertinib and sevabertinib are only approved for HER2–mutated NSCLC, T-DXd is indicated for HER2–mutated and HER2–overexpressing NSCLC. T-DXd was first approved for advanced NSCLC with HER2 mutations based on the phase 2 DESTINY-Lung02 trial. Later, the FDA expanded the approval for T-DXd to include all unresectable or metastatic solid tumors with HER2 IHC3+ overexpression based on the DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 trials

More recent trials such as DESTINY-Breast04 and DESTINY-Breast06 have shown that T-DXd is effective even in patients with lower HER2 expression, leading to the “HER2-low” and “HER2-ultralow” designations. Researchers are still exploring the mechanisms of T-DXd across different HER2 subgroups, and guidelines for interpreting HER2 positivity are rapidly evolving. For now, Dr. Caughron recommended following the HER2 interpretation guidelines established in gastric cancers when considering T-DXd for a patient with NSCLC.

T-DXd Side Effects

The panel briefly discussed the key toxicities associated with T-DXd in HER2–positive NSCLC. The most common side effects associated with T-DXd are nausea and fatigue, which may be managed with dose reductions. Oncologists should also incorporate antiemetic regimens to help manage nausea. Other less common side effects include neutropenia, alopecia, and cardiotoxicity. Oncologists should perform a baseline echocardiogram and repeat every 4 to 6 months to monitor for cardiac changes.

As with other antibody-drug conjugates, interstitial lung disease (ILD) is a rare but serious side effect of T-DXd that requires proactive management. Asymptomatic radiographic findings represent grade 1 ILD and call for holding T-DXd and initiating steroids, while grade 2 or higher ILD calls for full discontinuation. Overall, it is important to be familiar with appropriate prophylaxis and dose-modification strategies as the drug expands across disease sites and treatment settings, said Dr. Tarantino.